The present invention pertains to novel pharmacologically active trans-piperazin-1-yl-spiro[cyclohexane-1,1xe2x80x2-isobenzofuran] derivatives that are dopamine receptor subtype ligands having a preference for the D4-dopamine receptor. These compounds exhibit central dopaminergic activity, as defined below, and are useful in the treatment and/or prevention of disorders of the dopamine system, including schizophrenic and schizoaffective disorders, akinesia, dementia, Parkinson""s disease, nausea, bipolar disorders, emesis, tardive dyskinesia, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, hyperprolactemia and amenorrhoea.
The biological activity of only a few spirocyclic cylcohexane systems has been described. For example, in U.S. Pat. No. 3,932,425, U.S. Pat. No. 4,025,558 and U.S. Pat. No. 4,010,201, D. Lednicer refers to a series of spirocyclic cyclohexylamine derivatives that possess tranquilizing activity and are consequently useful in anxiety and schizophrenia and can be administered to reduce aggressive behavior and lower blood pressure. In U.S. Pat. No. 5,403,846, John J. Baldwin et al. refer to a series of spirocyclic benzopyrano cyclohexylamine derivatives that were studied for potassium channel blocking activity and found to exhibit type III antiarrythmic activity. In World Patent Application PCT/US95/05940, the same inventor, John J. Baldwin, refers to a series of spirocyclic dihydrobenzopyrano derivatives as constituting part of a combinatorial chemical library that contains ligands for potassium channels, adrenergic receptors, dopamine receptors and sigma-opioid receptors, and also refers to the use of this library for identifying biologically active agents such as, for example, inhibitors for carbonic acid anhydrase useful for treatment of glaucoma. Lawrence L. Martin describes, in J. Med. Chem., 24, pg. 617-621, 1981, the synthesis of a series of spiro isobenzofuran derivatives containing dialkylamino substituents and refers to the activity of these agents as centrally acting serotinergic agents. Similarly, William E. Parham describes, in J. Org. Chem., 41, pg. 2628-2633, 1976, the synthesis of a series of spiro[isobenzofuran-(3H),4xe2x80x2piperidine derivatives and biological activities that suggest their utility as antidepressant and antipsychotic agents. U.S. Pat. No. 5.352,678 refers to a series of dopaminergic cyclohexane derivatives and their use as antiischemic and antipsychotic agents.
U.S. Pat. No. 5,352,678, which issued on Oct. 4, 1994, refers to dopaminergic cyclohexane derivatives and to their utility as antiischemic and antipsychotic agents.
International Patent Application WO 94/19367, which was published on Sep. 1, 1994, refers to spiropiperidine derivatives and to their ability to increase endogenous hormone levels.
Thus, it is generally known that dopamine receptors are important for many functions in the animal body. For example, altered functions of these receptors are thought to participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure. Since these receptors control a great number of pharmacological events and, on the other hand, not all of them are presently known, it is possible that compounds acting preferentially on dopamine receptor subtypes, for example, on the D4 dopamine receptor, will exert a wide range of therapeutic effects in humans.
This invention relates to compounds of the formula 
wherein a is oxygen, CH2, C(CH3)2, NR10, sulfur, SO or SO2;
b is oxygen, CH2, Cxe2x95x90O, Cxe2x95x90NR11, Cxe2x95x90NOH, SO2, sulfur, SO, Cxe2x95x90NO(C1-C5)alkyl or CR7R8;
each of R1 through R8 is selected, independently, from hydrogen, halogen (e.q., chloro, fluoro, bromo or iodo), trifluoromethyl, cyano and hydroxy, or R7 and R8 together can be C(xe2x95x90O)NH2 or C(xe2x95x90O)N(C1-C4)alkyl, with the proviso that neither R7 nor R8 can be halo when a is oxygen, NR11, sulfur, SO or SO2; and
each of R10 and R11 is selected, independently, from hydrogen, benzyl and (C1-C6)alkyl;
and the pharmaceutically acceptable salts of such compounds.
Preferred compounds of the formula I are those wherein a is oxygen, b is CH2, each of R1, R4 and R5 is hydrogen, and each of R2, R3 and R6 is selected, independently from hydrogen, cyano, chloro and fluoro.
Other more specific embodiments of this invention include:
(a) compounds of the formula I wherein a is oxygen;
(b) compounds of the formula I wherein a is oxygen and b is CH2;
(c) compounds of th formula I wherein a is oxygen, b is CH2 and each of R1, R4 and R5 is hydrogen;
(d) compounds of the formula I wherein a is oxygen, b is CH2, each of R1, R4 and R5 is hydrogen and R3 is fluoro, cyano or chloro;
(e) compounds of the formula I wherein a is oxygen, b is CH2, each of R1, R4 and R5 is hydrogen and each of R2, R3 and R6 is selected, independently, from hydrogen, fluoro, cyano and chloro; and
(f) compounds of the formula I wherein a is oxygen, b is CH2, each of R1, R4 and R5 is hydrogen, and R2 and R3 are selected, independently, from fluoro, cyano and chloro.
The compounds of formula I above may contain chiral centers and therefore may exist in different enantiomeric forms. This invention relates to all optical isomers and all other stereoisomers of compounds of the formula I and mixtures thereof.
This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising an amount of a compound of the formula I, or pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition, and a pharmaceutical acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising a dopaminergic effective amount of a compound of the formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, and nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising an administering to said mammal a dopaminergic effective amount of a compound of the formula I, or pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition for treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission in a mammal, including a human, comprising a dopaminergic effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission in a mammal, including a human, comprising administering to said mammal a dopaminergic effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising a D4 receptor binding effective amount of a compound of the formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, dysphoric mania, schizophrenic and schizoaffective disorders, bipolar disorders, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, and nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising an administering to said mammal a D4 receptor binding effective amount of a compound of the formula I, or pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperthermia and amenorrhea in a mammal, including a human, comprising a D4 receptor binding effective amount of a compound of the formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.
The term xe2x80x9cdopaminergic effective amountxe2x80x9d, as used herein, refers to an amount of a compound sufficient to inhibit the binding of dopamine to a dopamine receptor with the effect of altering (i.e., increasing or decreasing) dopamine mediated neurotransmission.
The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of those compounds of formula I that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
This invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I.
The term xe2x80x9cone or more substituentsxe2x80x9d, as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, refers to radicals having the formula xe2x80x94O-alkyl, wherein xe2x80x9calkylxe2x80x9d is defined as above.
Compounds of the formula I and their pharmaceutically acceptable salts may be prepared as described below. In the reaction scheme and discussion that follows, a, b, R1 through R11 and structural formula I are defined as above. 
Schemes 1 and 2 illustrate methods of synthesizing compounds of the formula I.
Referring to scheme 1, a compound of the formula II is reacted with a compound of the formula III to form a compound of the formula I. This reaction is generally carried out in an inert solvent at a temperature from about 0xc2x0 C. to about 150xc2x0 C. preferably from about 0xc2x0 C. to about the reflux temperature of the solvent. Suitable solvents include water, cyclic and acyclic mono and dialkylamides (e.q., N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP), formamide and acetamide), (C1-C4)alkanols, halogenated hydrocarbon solvents (e.g., methylene chloride, chloroform and dichloroethane), acyclic and cyclic alkyl ethers (e.g., diisopropyl ether and tetrahydrofuran (THF)) and mixtures of two or more of the foregoing solvents.
Referring to scheme 2, a compound of the formula V, wherein Y is bromine, chlorine or iodine and L is a suitable group such as O-lithium, O-potassium, O-sodium, O-magnesium, xe2x80x94Oxe2x80x94(C1-C4)alkyl, N-Metal-phenyl wherein Metal is lithium, sodium, potassium or magnesium, xe2x80x94O-tri(C1-C4)alkylsilyl or xe2x80x94NH-phenyl, is cooled to about xe2x88x9280xc2x0 C. and converted into the corresponding compound wherein Y is lithium, potassium, sodium or magnesium, preferably lithium, using conventional methods (e.g., by addition of n-butyl lithium, t-butyl lithium or 2-methylpropyl lithium). After addition of the appropriate reagent, the reaction mixture is allowed to warm to room temperature. The resulting mixture containing the organometallic product of formula V is then cooled again to about xe2x88x9280xc2x0 C. and a compound of the IV is added to it, as depicted in the scheme, to form an intermediate of the formula VI, wherein Lxe2x80x2 and LGxe2x80x3 are the same or different and are selected from xe2x80x94OH, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94(C1-C4)alkyl, xe2x80x94O-tri(C1-C4)alkylsilyl, xe2x80x94NH2, xe2x80x94NH-phenyl, xe2x80x94Nxe2x80x94(C1-C4)alkyl, xe2x80x94SH, xe2x80x94S-trityl and xe2x80x94N-benzyl. The intermediate of formula VI can be converted into the corresponding compound of formula I via a ring closure step, as described below. Both the formation of the organometallic compound of formula V and the reaction of such compound with a compound of the formula IV are typically carried out in inert organic solvents such as cyclic or acyclic alkyl ethers (e.g., diisopropyl ether or THF) or mixtures of two or more such solvents.
The intermediate of formula VI can either be isolated or converted in situ into the desired compound of formula I. If the reaction mixture containing the intermediate is quenched with water, the intermediate will not react further and will be able to be isolated from the mixture by conventional methods. If, however, the mixture is refluxed with hydrochloric acid or another strong acid (e.g., sulfuric acid, nitric acid or sulfurous acid) at a temperature from about 0xc2x0 C. to about 150xc2x0 C., preferably at the reflux temperature, and contains an inert solvent selected from cyclic and acyclic mono and dialkylamides, acyclic alkyl ketones, (C1-C4)alkanols and mixtures of two or more such solvents, ring closure will occur, producing a compound of the formula I.
Alternate ring closure methods that can be used to form compounds of the formula I from the corresponding intermediates of formula VI are referred to by Martin, L. L., J. Med. Chem., 24, 617-621 (1981). This article is incorporated herein by reference in its entirety.
Scheme 3 illustrates a method of preparing the starting materials of formula II that are used in scheme 1. This method involves reacting the compound having formula VII with an organometallic compound of the formula V wherein Y is lithium, potassium, sodium or magnesium, preferably lithium. This reaction is typically carried out in a similar manner (and using similar solvents and conditions) to the reaction depicted in scheme 2 which forms the intermediate of formula VI. Thus, a compound of the formula V, wherein Y is chloro, bromo or iodo and L is defined as above, is cooled to a temperature of about xe2x88x9280xc2x0 C. and converted, using conventional techniques, into the corresponding compound wherein Y is lithium, potassium, sodium or magnesium, preferably lithium, and then allowed to warm to room temperature. The reaction mixture containing the organometallic product of formula V is then cooled again to about xe2x88x9280xc2x0 C. and a compound having formula VII is added to it to form an intermediate of the formula VIII, after which the mixture is again allowed to warm to about room temperature. As was the case for the process depicted in scheme 2, quenching the reacting mixture with water will prevent further reaction of the intermediate and allow it to be isolated, while refluxing with a strong acid will cause closure of the a-b-containing spirocyclic ring and hydrolytic removal of the ketal group to form the desired compound of formula II.
Compounds of the formula II wherein a is oxygen and b is oxygen or CH2 can be formed from the corresponding compounds of the formula VIII wherein Lxe2x80x2 and Lxe2x80x3 are hydroxy by treating the latter compound with a mineral acid (e.g., hydrochloric acid, phosphoric acid, sulfuric acid, perchloric acid, or nitric acid) in a mixture containing an inert solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic mono and dialkylethers, acyclic alkyl ketones, (C1-C4)alkanols and mixtures of two or more such solvents. The reaction temperature can range from about 0xc2x0 C. to about 150xc2x0 C., and is preferably about the reflux temperature of the reaction mixture.
The spirocyclic ring of compounds of the formula II can be formed, alternatively, by reacting a compound of the formula VIII, wherein b is CH2 and Lxe2x80x2 is hydrogen, with N-bromo, N-chloro or N-iodo succinimide in the presence of a radical generating agent (e.g., dibenzoyl peroxide or ultraviolet light). The corresponding compound of formula II is then formed by removing the ketal protecting group in intermediary products under acidic conditions.
The spirocyclic ring of compounds of the formula II wherein b is CH2 or oxygen and a is NH, N(C1-C4)alkyl or S can be formed, alternatively, from compounds of the formula VIII wherein b is CH2 or oxygen and Lxe2x80x2 and Lxe2x80x3 are selected, independently, from O-sulfonyl, xe2x80x94(C1-C5)alkyl, xe2x80x94O-sulfonylphenyl, halo and like substituents, by treating the latter compounds with the appropriate lower alkylamine, ammonia, benzylamine or sodium sulfide. This reaction is generally carried out in an inert organic solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic mono and dialkylethers, cyclic and acyclic alkylketones, (C1-C4)alkanols and mixtures containing two or more such solvents, at a temperature from about 0xc2x0 C. to about 150xc2x0 C., preferably at the reflux temperature.
Another process for the preparation of compounds of formula II wherein b is CH2 is illustrated in schemes 5 and 6 and described below. Starting with compounds of the formula XIII 
such compounds can be converted into compounds of the formula II in the presence of a trialkyltin-hydride such as, for example, tributyltinhydride and a radical generating reagent such as, for example, azo-bis-(isobutyronitrile) and by removing the ketal protecting group in the intermediary products under acidic conditions. This conversion can be carried out in a solvent such as benzene or toluene at a temperature ranging from about 25xc2x0 C. to about the reflux temperature. When protecting groups such as, for example, acetals are used, it may be convenient to remove such groups under acidic procedures. Similarly, other commonly used protecting groups may be introduced and removed using methods generally known to those skilled in the art.
Compounds of formula XIV may be prepared from the corresponding compounds having the general structure XIII 
The conversion of compounds having the general structure XIII into compounds of the formula XIV can be conveniently carried out in an inert organic solvent such as methylene chloride or chloroform, at temperature ranging from about xe2x88x9225xc2x0 C. to about the reflux temperature, in the presence of an (C1-C4)alkyl-sulfonylchloride and an acid acceptor such as an alkali carbonate, a tertiary amine or a similar reagent.
Intermediates of the formula XIII wherein, for example, b is oxygen, sulfur or amino, may be prepared by reacting compounds of the formula XII 
wherein Lxe2x80x2xe2x80x3 is bromo and b is hydroxy, mercapto or amino with a compound of the formula XI 
This reaction can be conveniently carried out in an inert organic solvent such as benzene, toluene, xylene, pyridine, collidine, methylene chloride or chloroform, at a temperature ranging from about 25xc2x0 C. to about the reflux temperature of the reaction mixture, in the presence of an acid acceptor such as an alkali carbonate, a tertiary amine or a similar reagent.
Compounds having the general formula XII are either commercially available or known in the literature. Compounds of the formula XI can be prepared from commercially available cyclohexanone derivatives and trialkylsulfonium derivatives using known methods such as those described by Rene Gree, Synthetic Communication, 15(8), 749-757 (1985).
Compounds of the formula V can be prepared from commercially available materials by known methods, e.g., as described by L. L. Martin in J. Med. Chem., 24, 617-621, 1981, referred to above. This reference is incorporated herein by reference in its entirety.
Scheme 4 illustrates the preparation of compounds of the formula IV, which are used as starting materials in the process depicted in scheme 2. Referring to scheme 4, a compound of the formula VII is first reacted with a compound of the formula III to form a compound of the formula X. This reaction is generally carried out using the same solvents and conditions described above for the reaction depicted in scheme 1 (i.e., the formation of compounds of the formula I from the reaction of compounds of the formulae II and III). Thus, compounds embraced in general formula X may be prepared by reacting compounds having the general formula III with the cyclohexanone derivative of formula VII in a solvent selected from water, cyclic and acyclic mono and dialkylamides, (C1-C4)alkanols, halogenated solvents, acyclic and cyclic alkylethers and mixtures of two or more such solvents at temperatures ranging from 0xc2x0 C. to about 150xc2x0 C. preferably from about 0xc2x0 C. to about the reflux temperature of the reaction mixture.
Compounds of the general formula IV may be prepared by hydrolysing compounds with general formula X with an aqueous mineral acid in a solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic mono and dialkylethers, cyclic and acyclic alkylketones, (C1-C4)alkanols and mixtures of two or more such solvents at temperatures ranging from about 0xc2x0 C. to about 150xc2x0 C., preferable at the reflux temperature of the mixture.
Compounds with general formula III may be prepared by reacting piperazine derivatives with an appropriate aryl transferring group in a solvent selected from cyclic and acyclic mono and dialkylamides, (C1-C4)alkanols, cyclic and acyclic alkylethers, cyclic and acyclic alkylesters, cyclic and acyclic alkylketones, pyridine derivatives, halogenated solvents and mixtures of two or more such solvents at temperatures ranging from about 0xc2x0 C. to about 150xc2x0 C., preferably from about 0xc2x0 C. to about the reflux temperature of the mixture. Addition of acid acceptors such as an alkali carbonates, tertiary amines or similar reagents as well as the addition of dehydrating reagents may be useful.
An alternate method of preparing compound of the formula I is illustrated in Scheme 7.
Referring to Scheme 7, a compound of formula XIX may be prepared by reacting a compound of formula XVIII, wherein PG is a nitrogen protecting group, with compound of the formula II, in water or an inert organic solvent such as those selected from polychlorinated C1-C2 alkanes, cyclic and acyclic mono and dialkylamides (e.g., N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP), formamide and acetamide), (C1-C4)alkanols, halogenated hydrocarbon solvents (e.g., methylene chloride, chloroform and dichloroethane), acyclic and cyclic alkyl ethers (e.g., diisopropyl ether and tetrahydrofuran (THF)) and mixtures of two or more of the foregoing solvents, at temperatures ranging from about 0xc2x0 C. to about 150xc2x0 C., preferably at 0xc2x0 C. or the boiling point of the solvent mixture.
Compounds of formula XX can then be prepared by deprotecting a compound of general formula XIX according to a method suitable to the protecting group selected. For example, when the protecting group is benzyl, trityl, benzhydryl or carbobenzyloxy, deprotection may be accomplished by hydrogenation in presence of a catalyst, in a solvent in selected from water and inert organic solvents, such as those selected from cyclic and acyclic mono and dialkylamides, (C1-C4) alcohols, acyclic and cyclic alkylethers and mixtures of two or more of the foregoing solvents, at temperatures ranging from about 0xc2x0 C. to about 150xc2x0 C. When the protecting group is tertiarybutoxycarbonyl or benzyloxycarbonyl, deprotection may be accomplished by treating a compound of formula XIX with an acid in water or an inert organic solvent such as those selected from cyclic and acyclic mono and dialkylamides, (C1-C4) alcohols, acyclic and cyclic alkylethers, and mixtures of two or more of the foregoing solvents, at temperatures ranging from about 0xc2x0 C. to about 150xc2x0 C.
Compounds of general formula I can be prepared by reacting a compound of the formula XX with an appropriate aryl transferring group in water or an inert organic solvent, such as those selected from cyclic and acyclic mono and dialkylamides, C1-C4 alcohols, cyclic and acyclic alkylethers, cyclic an acyclic alkylesters, cyclic and acyclic alkyletones, pyridine derivatives, halogenated hydrocarbons, and mixtures of two or more of the foregoing solvents, at temperatures ranging from about 0xc2x0 C. to 150xc2x0 C., preferable from about 0xc2x0 C. or the to the reflux temperature of the solvent mixture. addition of acid acceptors such as an alkali carbonates, tertiary amines or similar reagents as well as the addition of dehydrating reagents may be useful.
Compounds embraced in general formula III are either commercially available or can be prepared by reacting known piperazine derivatives with aryl transferring reagents. Thus, these reactions can be conveniently carried out in water or an inert organic solvent such as those selected from alcohols, pyridine, cyclic and acyclic alkylketones, cyclic and acyclic alkylesters, cyclic and acyclic alkylethers, cyclic and acyclic mono and dialkylamides, and mixtures of two or more of the foregoing solvents, at temperatures ranging from xe2x88x9280xc2x0 C. to 150xc2x0 C. Addition of acid acceptors such as an alkali carbonates, tertiary amines or similar reagents, as well as the addition of dehydrating reagents, may be useful.
The reaction of arylmetal compounds with cyclohexanone derivatives is preferably performed at a temperature from about xe2x88x9280xc2x0 C. to about 0xc2x0 C. All other reaction steps are preferable carried out at temperatures ranging from about 0xc2x0 C. to about the reflux temperature of the solvent. When ketone protecting groups such as acetals are employed, it may be convenient to remove these groups using acidic reaction conditions. Similarly, other commonly used protecting groups may be introduced and removed according to methods generally known to someone skilled in the art.
The preparation of other compounds of the formula I not specifically described in the foregoing discussion section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in schemes 1 to 7 above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 4 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
The novel compounds of the formula I and their pharmaceutically acceptable salts (hereinafter xe2x80x9cthe therapeutic compounds of this inventionxe2x80x9d) are useful as dopaminergic agents, i.e., they possess the ability to alter dopamine mediated neurotransmission in mammals, including humans. They are therefore able to function as therapeutic agents in the treatment of a variety of conditions in mammals, the treatment or prevention of which can be effected or facilitated by an increase or decrease in dopamine mediated neurotransmission. Such conditions include psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, emesis, nausea, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, hyperdermia and amenorrhea.
The compounds of the formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
The therapeutic compounds of this invention can be administered orally, transdermally (e.g., through the use of a patch), parenterally or topically. Oral administration is preferred. In general, these compounds are most desirably administered in dosages ranging from about 0.01 mg up to about 250 mg per day, although variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The D4 dopaminergic activity of the compounds of the present invention may be determined by the following procedure.
The determination of D4 dopaminergic activity has been described by Van Tol et al., Nature, vol. 350, 610 (London, 1991). Clonal cell lines expressing the human dopamine D4 receptor are harvested and homogenized (teflon pestle) in a 50 mM Tris.HCl (pH 7.4 at 4xc2x0 C.) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCl2), 5 mM magnesium chloride (MgCl2), 5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl). The homogenates are centrifugated for 15 min. at 39,000 g, and the resulting pellets resuspended in a buffer at a concentration of 150-250 xcexcg/ml. For saturation experiments, 0.25 ml aliquots of tissue homogenate are incubated in duplicate with increasing concentrations of [3H]Spiperone (70.3 Ci/mmol; 10-3000 pM final concentration) for 30-120 minutes at 22xc2x0 C. in a total volume of 1 ml. For competition binding experiments, assays are initiated by the addition of 0.25 ml of membrane and incubated in duplicate with the indicated concentrations of competing ligands (10xe2x88x9214-10xe2x88x9213 M) and [3H]Spiperone (100-300 pM) in either the absence or presence of 200 uM GPP(NH)p (5xe2x80x2/guanylylimidodiphosphate), where indicated, for 60-120 min at 22xc2x0 C. Assays are terminated by rapid filtration through a Titertek cell harvester and the filters subsequently monitored for tritium as described by Sunahara, R. K. et al., Nature, 346, 76-80 (1990). For all experiments, specific [3H]Spiperone binding is defined as that inhibited by 1-10 xcexcM (+) Butaclamole or 1 xcexcM Spiperone. Both saturation and competition binding data are analyzed by the non-linear least square curve-fitting program Ligand run on a digital Micro-PP-11 as described by Sunahara et. al.